Beta-carbolines, process for their production and their use in pharmaceutical agents

ABSTRACT

Compounds of formula I ##STR1## in which R A , B (which is CR 4 ) and R 3  and have the meaning indicated in the application, as well as their production and their use in pharmaceutical agents, are described.

The invention relates to new beta-carbolines, their production and usein pharmaceutical agents.

From numerous publications, such as, for example, from EP-A-54507, it isknown that beta-carbolines influence the central nervous system and aresuitable as psychopharmacological agents. Surprisingly, it was shownthat the beta-carbolines, substituted in 3-position according to theinvention, are bio-available over a longer period and at the same timeexhibit a good affinity for the benzodiazepine receptors.

The compounds according to the invention have general formula I ##STR2##in which R^(A) means halogen, --CHR¹ -R², phenyl or OR⁵ and can besingle or double and

R^(A) represents hydrogen or C₁₋₄ alkyl,

R² represents hydrogen, C₁₋₄ alkyl, --O--C₁₋₄ alkyl or an optionallysubstituted phenyl, benzyl or phenoxy radical, and

R⁵ represents hydrogen, tri-C₁₋₄ -alkylsilyl, C₁₋₄ alkyl, C₃₋₇cycloalkyl or an optionally substituted phenyl, benzyl or hetarylradical and

B is nitrogen or CR⁴ and

R⁴ is hydrogen, C₁₋₄ alkyl or C₁₋₄ alkoxy-C₁₋₂ alkyl and

R³ is --CO--R or --CHOH--R and R represents an optionally substitutedmonocyclic or bicyclic aryl or hetaryl radical or a C₃₋₁₀ cycloalkyl orbicycloalkyl radical as well as their isomers and acid addition salts.

Substituent R^(A) can be in the A-ring in 5- to 8-position, preferablyin 5-, 6- or 7-position.

Alkyl in each case contains both straight-chain and branched-chainradicals, such as, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl and tert-butyl.

By halogen is understood, respectively, fluorine, chlorine, bromine andiodine.

Cycloalkyl in each case can stand for cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and2-methyl-cyclopropyl, and 3-5 carbon atoms are preferred for substituentR⁵.

If R⁵ means a hetaryl radical, the latter is 5- or 6-membered andcontains 1-2 heteroatoms, such as nitrogen, oxygen and/or sulfur. Forexample, the following 5- and 6-ring heteroaromatic compounds can bementioned: pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene,pyrrole, thiazole, imidazole.

Heterocycles containing nitrogen and substituted with halogen canoptionally be considered as preferred hetaryl radicals R⁵.

The substituent of phenyl, benzyl and hetaryl radical R⁵ can be singleto triple in any position. Suitable substituents are halogens, nitro,cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, amino and C₁₋₄ alkoxycarbonyl, and inparticular fluorine, chlorine and bromine are preferred.

As substituents of phenyl, benzyl and phenoxy radical R², thesubstituents of the aromatic compounds, mentioned for R⁵, are suitable,in particular halogens such as chlorine and bromine.

The aryl and hetaryl radical in R³ can be present as a monocyclic orbicyclic compound and can contain 5-12 ring atoms, preferably 5-9 ringatoms, such as, for example, phenyl, biphenylyl, naphthyl, indenyl asaryl radical, and thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl, pyridyl,pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, thiazolyl,isothiazolyl, quinolyl, isoquinolyl, benzo[1]thienyl, benzofuryl ashetaryl radical with 1-2 heteroatoms, such as sulfur, oxygen and/ornitrogen.

The substituent of aryl and hetaryl radical R can be single to doubleand can be halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, amino or nitro, andC₁₋₄ alkyl, C₁₋₄ alkoxy and amino are preferred.

By a bicycloalkyl radical R is understood, for example, bicycloheptyland bicyclooctyl.

If a chiral center is present, the compounds of formula I can be presentin the form of diastereomers and their mixtures.

The physiologically compatible acid addition salts are derived from theknown inorganic and organic acids, such as, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid,acetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid,tartaric acid, citric acid, oxalic acid, glyoxylic acid as well as fromalkanesulfonic acids and arylsulfonic acids, such as, for example,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, i.a.

As especially preferred embodiments for R, the cycloalkyls, mentioned atthe beginning, with 3-5 carbon atoms as well as optionally substitutedphenyl, biphenyl, naphthyl and thienyl can be considered.

The compounds of formula I as well as their acid addition salts areusable because of their affinity for benzodiazepine receptors aspharmaceutical agents and have antagonistic, inversely agonistic andagonistic effects on the properties known of the benzodiazepines. At thesame time, the compounds according to the invention show an extendedduration of action.

By the example of the 3-benzoyl derivative in comparison with the3-carboxylic acid phenyl ester derivative, it can be gathered from thetable below that the compounds according to the invention not onlyexhibit a higher stability relative to hepatic enzymes, but also have abetter affinity, especially a better in vivo affinity, forbenzodiazepine receptors. The affinity is determined by examining thedisplacement capacity of radioactively-labeled flunitrazepam from thebenzodiazepine receptors.

The ED₅₀ value represents the dose of a test substance, which bringsabout a reduction of the specific binding of the flunitrazepam to thebenzodiazepine receptor in a living brain to 50% of the control value.

The in vivo test is performed as follows:

The test substance is injected in varying doses and normallyintraperitoneally in groups of mice. After 15 minutes, the ³H-flunitrazepam is administered intravenously to the mice. After another20 minutes, the mice are killed, their forebrains are removed, and theradioactivity specifically bound to the brain membranes is measured byscintillation counting. The ED₅₀ value is determined from thedose-effect curves.

The metabolic stability is determined by a homogenate of hepatic tissuein physiological common salt solution being incubated with the testsubstance for 0 or 2 hours at 37° C. Then, the incubation batch isextracted and the content of test substance in the extract is determinedby HPLC/fluorimetry. The substance remaining after 2 hours in comparisonwith 0 hours is expressed in percent stability.

    ______________________________________                                        Inhibition of the H.sup.3 -BD binding Metabolic Stability                     In vivo         Human liver homogenate                                        ED.sub.50 mg/kg 2 hours at 37° C.                                      ______________________________________                                        A       5.0         72%                                                       B       greater than 90                                                       ______________________________________                                         A = 6benzyloxy-4-methoxymethyl-3-benzoyl-beta-carboline                       B = 6benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylic acid phenyl        ester                                                                    

The compounds according to the invention are further distinguished byanxiolytic and anticonvulsive effectiveness.

To examine the anxiolytic effect, the compounds are tested in the4-plate test according to the method of Boissier et al., Eur. J.Pharmacol. 4, 145-150 (1968). In this case, the minimal effective dose(MED) is indicated, which increases the locomotor activity of theafflicted mice after intraperitoneal treatment. A reduction of theactivity in the 4-plate test without being afflicted indicates sedativeproperties.

The compounds of formula I are suitable in particular for treatment ofanxiety accompanied by depressions, epilepsy, sleep disturbances,spasticities and muscle relaxation during anesthesia and also showamnestic or memory-promoting properties.

To use the compounds according to the invention as pharmaceuticalagents, the latter are put in the form of a pharmaceutical preparation,which, besides the active ingredient for the enteral or parenteraladministration, contains suitable pharmaceutical, organic or inorganicinert vehicles, such as, for example, water, gelatin, gum arabic,lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, etc.

The pharmaceutical preparations can be present in solid form, forexample, as tablets, coated tablets, suppositories, capsules or inliquid form, for example, as solutions, suspensions or emulsions.Optionally, they also contain auxiliary agents, such as preservatives,stabilizers, wetting agents or emulsifiers, salts to change the osmoticpressure or buffers.

For parenteral administration, in particular injection solutions orsuspensions, in particular aqueous solutions of the active compounds inpolyhydroxyethoxylated castor oil, are suitable.

As vehicle systems, surface-active auxiliary agents such as salts of thebile acids or animal or plant phospholipids, but also their mixtures aswell as liposomes or their components, can also be used.

For oral application, in particular tablets, coated tablets or capsuleswith talc and/or hydrocarbon vehicles or binding agents, such as, forexample, lactose, corn starch or potato starch, are suitable. Theapplication can also take place in liquid form, such as, for example, asjuice, to which a sweetener is optionally added.

The compounds according to the invention are introduced in a dosage unitof 0.05 to 100 mg of active substance in a physiologically compatiblevehicle.

The compounds according to the invention are generally used in a dose of0.1 to 300 mg/day, preferably 0.1 to 30 mg/day, especially preferably1-20 mg/day, for example, as anxiolytic agents analogous to diazepam.

The production of the compounds according to the invention can beperformed according to methods known in the art. For example, compoundsof formula I are attained, in that compounds of formula II ##STR3## inwhich R^(A) and B have the above-mentioned meaning and

R⁹ is hydrogen or a protecting group and

Y is cyano or --CO--Z and

Z is hydrogen, C₁₋₄ alkoxy or an acid derivative, are reacted with ametallo-organic compound R-Me

and then optionally a trialkylsilyl group is cleaved to the hydroxygroup is etherified to R^(A) =OR⁵ or R³ meaning --CH--OH--R is oxidizedto the ketone or the protecting groups are cleaved or the isomers areseparated or the acid addition salts are formed.

For example, a Grignard compound, such as R-Mg-halogen, or alithium-organic compound R-Li is suitable as a metallo-organic compound.For the reaction with the metallo-organic compound, suitable acidderivatives are, for example, carboxylic acid amides --NR⁷ R⁸, in whichR⁷ represents C₁₋₄ alkyl and R⁸ represents C₁₋₄ alkyl or C₁₋₄ alkoxy orR⁷ and R⁸ together with the nitrogen atom form an imidazole.

The reaction with the metallo-organic compound can be performed attemperatures of -70° C. up to room temperature in aprotic polarsolvents, such as cyclic and acyclic ethers or hydrocarbons. Forexample, as a suitable solvent, there can be mentioned diethyl ether,tetrahydrofuran, dioxane, toluene, hexane, i.a.

As protecting groups R⁹, all protecting groups usually used aresuitable, such as, for example, alkyl, alkanoyl, aralkyl, arylsulfonyl,alkylsulfonyl or silyl radicals, and sulfonyls, such as tosyl and mesyland trialkylsilyls, such as tert-butyldimethylsilyl, trimethylsilyl andtert-butoxycarbonyl, are preferred.

If a protecting group R⁹ or tri-C₁₄ alkylsilyloxy group R^(A) is presentin the compounds of formula I, the latter can be cleaved with the usualmethods, such as, by treatment with bases, such as sodium or potassiumhydroxide or alcoholate, or acids, such as dilute mineral acid,trifluoroacetic acid or tetrabutylammonium fluoride, optionally duringthe working up of the reaction mixture, at room temperature or highertemperature.

If the compounds according to the invention with R^(A) meaning OH areetherified, the methods described in EP-237467, EP-A-234173 andEP-A-130140 can be used, by, for example, a reactive derivative R⁵ x, inwhich x is halogen, tosylate, mesylate or triflate, being reacted in thepresence of a base in a polar solvent.

If the compounds of formula I contain R³ meaning a --CHOH--R group, thelatter can be oxidized to a --CO--R group, by being oxidized optionallyin the presence of an organic base such as pyridine, triethylamine withoxalyl chloride or with an oxidizing agent such as manganese dioxide,pyridine chlorochromate, chromium oxide, iron (III) chloride oraccording to the Oppenauer method or by being dehydrogenated in thepresence of a copper catalyst. Also, oxidation with azodicarboxylic acidester is possible, for example, analogously to F. Yoneda et al., J. Org.Chem. 32, 727 (1967).

The reaction can be performed at room temperature or higher temperatureup to boiling temperature of the reaction mixture in an inert solvent,such as chlorinated hydrocarbons, hydrocarbons, acetone, alcohols suchas tert-butanol.

The mixture of isomers can be separated according to the usual methods,such as, for example, crystallization, chromatography or salt formationin the diastereomers or enantiomers.

For the formation of physiologically compatible acid addition salts, acompound of formula I is dissolved, for example, in a little alcohol andmixed with a concentrated solution of the desired acid.

In so far as the production of the initial compounds is not described,their method of production is known or analogous to that of knowncompounds or the latter can be produced analogously to processesdescribed here.

For example, the production of the 3-formyl derivative of formula II cantake place analogously to the methods described in Ep-A-216541 andEP-A-305322. The production of 3-carboxylic acid esters and theirreactive acid derivatives is described, for example, in EP-A-54507,EP-A-237467, EP-A-234173, EP-A-137390, EP-A-23966 and EP-A-222693. Theproduction of the nitriles takes place, for example, according to theprocess described in EP-A-234137.

The following examples are to explain the process according to theinvention.

Production of the initial compounds A)6-Benzyloxy-4-methoxymethyl-bea-carboline-3-carboxylic aciddimethylamide

Dimethylamine was introduced for 5 minutes in a solution of 1.0 g of6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylic acid imidazolidein 25 ml of dimethylformamide. Then, it was diluted with ethyl acetateand washed with water, dried, filtered and concentrated by evaporation.The residue was recrystallized from ethyl acetate and yielded 680 mg ofthe title compound of melting point of 174°-176° C.

B) 6-Benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylic acidimidazolide

1.34 g of 6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylic acidwas mixed in 50 ml of absolute tetrahydrofuran at room temperature with45 ml of a freshly prepared 0.27 molar thionyl diimidazole solution intetrahydrofuran and stirred for 2 hours with exclusion of moisture.After distilling off the solvent, it was taken up in ethylacetate/water, washed twice with water and once with saturated sodiumchloride solution. The ethyl acetate phase was dried, concentrated byevaporation and the resulting crude product was absorptivelyprecipitated with ethyl acetate.

1.31 g of the title compound with melting point 184°-185° C. wasobtained.

Analogously, there are produced:

6-(2-pyrazinyloxy -4-methoxymethyl-beta-carboline-3-carboxylic acidimidazolide

5-(4-chlorophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acidimidazolide

5-(4-fluorobenzyloxy)-4-methoxymethyl-beta-carboline-3-carboxylic acidimidazolide

EXAMPLE 16-Benzyloxy-3-cycloproxylcarbonyl-4-methoxymethyl-betacarboline

18 ml of a 0.5 molar solution of cyclopropylmagnesium bromide intetrahydrofuran was instilled in 618 mg of6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylic acid imidazolidein 45 ml of absolute tetrahydrofuran at -6° to -10° C. in about 10minutes and stirred for 1 hour under ice cooling. After 16 hours ofreaction time at room temperature, it was weakly acidified with diluteHCl solution, concentrated by evaporation and extracted with methylenechloride. The organic phase was washed with water, saturated sodiumbicarbonate solution and saturated sodium chloride solution, dried andconcentrated by evaporation. 133 mg of the title compound with meltingpoint of 133° C. was obtained by column chromatography on silica gelwith methylene chloride/ethanol 2:1 and recrystallization from ethylacetate/petroleum ether.

Analogously, there are obtained:

6-benzyloxy-4-methoxymethyl-3-(1-naphthyl)-carbonyl-beta-carboline,melting point 223°-224 C. (ethyl acetate, ethanol hexane)

6-benzyloxy-3-(2-methylcyclopropylcarbonyl)-4-methoxymethyl-beta-carboline

5-(4-chlorophenoxy)-3-cyclopropylcarbonyl-4-methoxymethyl-beta-carboline

6-benzyloxy-3-(cyclobutylcarbonyl)-4-methoxymethyl-beta-carboline,melting point 153°-154 C. (ethyl acetate, hexane)

6-(2-pyrazinyloxy)-3-cyclopropylcarbonyl-4-methoxymethyl-beta-carboline,melting point 167°-169° C. (ethyl acetate/hexane)

5-(4-fluorobenzyloxy-3-cyclopropylcarbonyl)-4-methoxymethylbeta-carboline

EXAMPLE 2 6-Benzyloxy-4-methoxymethyl-3-benzoyl-beta-carboline

A solution of 1.09 g of6-benzyloxy-4-methoxymethyl-9-tosyl-beta-carboline-3-carboxylic acidisopropyl ester isopropyl ester in 20 ml of absolute tetrahydrofuran wasmixed at -60° C. under argon with 2.1 ml of a 1.08 molar phenyllithiumsolution in ether/hexane, stirred for 1 hour at -60° C. and then heatedslowly to room temperature. After 3 hours of reaction time at roomtemperature, it was acidified with nHCl and the solvent was distilledoff. After taking up in ethyl acetate/water, the organic phase wasseparated, washed with saturated sodium chloride solution, dried andconcentrated by evaporation. 435 mg of the title compound was obtainedby crystallization of ethanol/petroleum ether, melting point 167°-168°C.

Analogously, there are obtained:

6-benzyloxy-4-methoxymethyl-3-(thiophen-2-yl)-beta-carboline, meltingpoint 165° C. (ethyl acetate/petroleum ether)

6-benzyloxy-4-methoxymethyl-3-(2-methoxybenzoyl)-beta-carboline, meltingpoint 145°-146 C. (ethyl acetate/petroleum ether)

3-benzoyl-6,7-dimethoxy-4-ethyl-beta-carboline, melting point 182°-184°C. (methylene chloride/ethanol), from6,7-dimethoxy-4-ethyl-9-tosyl-beta-carboline-3-carboxylic acid ethylester, 3-benxyl-5-bezyloxy-4-methoxymethyl-beta-carboline, melting point195°-198° C. (cyclohexane/ethyl acetate), from5-oxy-4-methoxymethyl-9-tosyl-beta-carbolxylic acid ethyl ester, meltingpoint 149°-150° C. (ethyl acetate)

3-benzoyl-5-isopropoxy-4-methyl-beta-carboline, melting point 234°-235°C. (cyclohexane/ethyl acetate), from5-isopropoxy-4-methyl-9-tosyl-beta-carboline-3carboxylic-3-carboxylicacid methyl ester, melting point 160°-161° C. (isopropanol) meltingpoint 197°-198° C. (ethyl acetate)

3-benzoyl-5-(4-fluorobenzyloxy)-4-methoxymethyl-beta-carboline, meltingpoint 213°-214° C., from5-(4-fluorobenzyloxy)-4-methoxymethyl-9-tosyl-beta-carboline-3-carboxylic acid ethyl ester 149°-150° C.

3-[(2-methyl)-benzoyl]-6-benzyloxy-4-methoxymethyl-beta-carboline,melting point 164° C. (ethyl acetate, ethanol, hexane)

3-(4-phenylbenzoyl)-6-benzyloxy-4-methoxymethyl-beta-carboline, meltingpoint 108°-109° C. (ethyl acetate, ethanol, hexane)

3-benzoyl-4-methoxymethyl-5-(4-chlorophenoxy)-beta-carboline, meltingpoint 238°-240°C. (methylene chloride, ethyl acetate, hexane), from5-(4-chlorophenoxy)-4-methoxymethyl-9-tosyl-beta-carboline-3-carboxylicacid isopropyl ester of melting point 185°-187° C.

EXAMPLE 3

2-Benzoyl-8-phenoxy-5H-pyrimido[5,4-blindole

Analogously to example 2, the title compound is obtained from8-phenoxy-5-tosyl-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethylester, melting point 251°-253° C. (ethyl acetate).

Production of the initial material:

Analogously to the synthesis described by K. Clarke, W. Richard and R.M. Scrowston, J. Chem. Res. 1980 (2) 833-847,2-amino-5-phenoxy-benzonitrile is converted to3-amino-4-phenoxy-1-tosylindole-2-carbonitrile, which, analogously tothe process described in EP-A-115248, is converted to8-phenoxy-5-tosyl-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl etherwith melting point 136°-139° C. (ethanol).

EXAMPLE 4 3-Benzoyl-5-ethoxymethyl-beta-carboline

Analogously to example 2, the title compound is obtained from5-ethoxymethyl-9-tosyl-beta-carboline-3-carboxylic acid ethyl ester,melting point 195°-197° C. (ethyl acetate).

Production of the initial material:

By tosylation of 5-ethoxymethyl-beta-carboline-3-carboxylic acid ethylester, known from Ep-110813, melting point 142°-143° C. (ethanol).

EXAMPLE 5 3-Benzoyl-4,5-diethyl-beta-carboline

Analogously to example 2, the title compound is obtained from4,5-dimethyl-9-tosyl-beta-carboline-3-carboxylic acid ethyl ester,melting point 208°-209° C. (ethyl acetate).

The production of the initial compounds takes place by knownesterification and tosylation of4,5-dimethyl-beta-carboline-3-carboxylic acid.

EXAMPLE 6

3-Benzoyl-5-ethoxymethyl-4-methoxymethyl-beta-carboline

Analogously to example 2, the title compound is obtained from5-ethoxymethyl-4-methoxymethyl-9-tosyl-beta-carboline-3-carboxylic acidethyl ester, melting point 180°-182° C. (ethanol).

The production of the initial material takes place by tosylation of5-ethoxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethylester known from EP-A-161575, melting point 90°-92° C. (ethanol).

EXAMPLE 7

3-Benzoxy-4-methoxymethyl-6-triisoproylsilyloxy-beta-carboline

A solution of 230 mg of4-methoxymethyl-9-tosyl-6-triisopropylsilyloxy-beta-carboline-3-carboxylicacid isopropyl ester in 3.5 ml of absolute tetrahydrofuran was mixed at-60° C. under argon with 0.38 ml of a 1.08 molar phenyllithium solutionin ether/hexane, stirred for 1 hour at -60° C. and heated slowly to roomtemperature. After 16 hours of standing at room temperature, thereaction mixture was mixed with N-acetic acid/ethyl acetate, the ethylacetate phase was washed with water and saturated sodium chloridesolution, dried and concentrated by evaporation. After columnchromatography on silica gel with cyclohexane/ethyl acetate 1:1 aseluant, 69 mg of title compound was obtained.

Production of the initial material A)4-Methoxymethyl-6-(tripsoropylsilyloxy)-beta-carboline-carboxylic acidisopropyl ester

314 mg of 6-hydroxy-4-methoxymethyl-beta-carboline-3-carboxylic acidisopropyl ester was stirred in 20 ml of dichloromethane with 61 mg of4-dimethylaminopyridine, 0.31 ml of triethylamine and 425 mg ofchlorotriisopropylsilane for 7 hours at room temperature. Then, it waswashed with water and saturated common salt solution, the organic phasewas dried and concentrated by evaporation. After purification of thecrude product on a silica gel column with dichloromethane/ethanol 10:1as eluant and recrystallization from ether/petroleum ether, 392 mg ofthe desired compound was obtained, melting point 144°-145° C.

B)4-Methoxymethyl-9-tosyl-6-(triisopropylsilyloxy)-beta-carboline-3-carboxylicacid isopropyl ester

1 g of4-methoxymethyl-6-(triisopropylsilyloxy)-beta-carboline-3-carboxylicacid isopropyl ester, 132 mg of 4-dimethylaminopyridine and 0.45 ml oftriethylamine were mixed in 10 ml of dichloromethane at about 4° C. with615 m of tosyl chloride and then stirred at room temperature for 1 hour.After 16 hours of standing at room temperature, it was diluted withdichloromethane and washed with saturated sodium bicarbonate solutionand saturated sodium chloride solution. After chromatography on silicagel in the system of cyclohexane/ethyl acetate 1:1, 1.32 g of the titlecompound was obtained from the isolated organic phase.

EXAMPLE 8

3-Benzoyl-6-hydroxy-4-methoxymethyl-beta-carboline

530 mg of3-benzoyl-6-triisopropylsilyloxy-4-methoxymethyl-beta-carboline wasdissolved in 7.5 ml of absolute tetrahydrofuran and stirred for 0.5 hourunder argon at room temperature after adding 1.1 ml of a 1.1 molartetrabutylammonium fluoride solution in tetrahydrofuran. After addingethyl acetate, the organic phase was washed with saturated common saltsolution, dried and concentrated by evaporation. 315 mg of the titlecompound was obtained after absorptive precipitation with ethylacetate/petroleum ether, melting point 258° C.

EXAMPLE 93-Benzoyl-6-(5-bromopyridin-2-yloxy)-4-methoxymethyl-beta-carboline

332 mg of 3-benzoyl-6-hydroxy-4-methoxymethyl-beta-carboline and 130 mgof potassium hydroxide powder were mixed in 3 ml of dimethyl sulfoxideunder argon with 285 mg of 2,5-dibromopyridine in 1 ml of dimethylsulfoxide and heated for 1 hour to 90°-95° C. The reaction mixture waspoured on ice water, acidified with 1N-acetic acid to pH 5 and shakenout with ethyl acetate. The ethyl acetate phase was washed withsaturated common salt solution, dried on magnesium sulfate andconcentrated by evaporation. After chromatography on silica gel withdichloromethane/ethyl acetate 1:1 as eluant and recrystallization fromthe main fraction from ethyl acetate/petroleum ether, the title compoundwith melting point 193°-194° C. was obtained.

EXAMPLE 10

6-Benzyloxy-3-(1-hydroxy-1-phenylmethyl)-4-methoxymethyl-beta-carboline

300 mg of6-benzyloxy-3-(1-hydroxy-1-phenylmethyl)4methoxymethyl-9-(4-methylphenylsulfonyl)-beta-carbolinewas added a sodium methylate solution of 50 mg of 80% sodium hydride and30 ml of absolute ethanol and refluxed for 2 hours under argon. Afterdistilling off the solvent, the residue was taken up in ethyl acetateand washed with saturated sodium chloride solution. After columnchromatography on silica gel in the system of dichloromethane/ethanol12:1, 211 mg of the title compound was obtained after recrystallizationfrom ethyl acetate/petroleum ether from the ethyl acetate phase dried onmagnesium sulfate and concentrated by evaporation, melting point190°-191° C.

Analogously, there are obtained:

6-Benzyloxy-3-(1-hydroxy-1-cyclopentylmethyl)-4-methoxymethyl-beta-carbolin

Production of the initial material6-Benzyloxy-3-(1-hydroxy-1-phenylmethyl)-4-methoxymethyl-9-(4-methylphenylsulfonyl)-beta-carboline

A solution of 1.0 g of 6-benzyloxy-3-formyl-4-methoxymethyl-9-(4-methylphenylsulfonyl)-beta-carboline in 60 ml of absolutetetrahydrofuran was mixed at -60° C. under argon with 2.4 ml of a 1.08molar phenyllithium solution in ether/hexane, stirred for 1 hour at -60°C. and then heated slowly to room temperature. After taking up in ethylacetate/water, the organic phase was separated, washed with saturatedsodium chloride solution, dried and concentrated by evaporation. Aftercolumn chromatography on silica gel with the eluantsdichloromethane/ethanol 15:1 and cyclohexane/ethyl acetate 1:1, 717 mgof the title compound was obtained with melting point 169°-171° C.

Analogously, there are obtained:

With cyclopentylmagnesium bromide,6-benzyloxy-3-(1-hydroxy-1-cyclopentylmethyl)-4-methoxymethyl-9-(4-(4-methylphenylsulfonyl)-beta-carboline, melting point 146°-147° C.(ethyl acetate, ethanol, hexane).

EXAMPLE 11

3-Benzoyl-5-(2-chlorophenoxymethyl)-4-methoxymethyl-beta-carboline

Analogously to example 2, the title compound is obtained from5-(2-chlorophenoxymethyl)4-methoxymethyl-9-tosyl-betacarboline-3-carboxylicacid ethyl ester, melting point 149°-152° C. (ethanol).

Production of the initial material a) 4-(2-Chlorophenoxy)-methylindole

A solution of 4-hydroxymethylindole (1.0 g) in tetrahydrofuran (10 ml)is instilled in a solution of triphenylphosphine (2.92 g),2-chlorophenol (1.43 g) and azodicarboxylic acid diethyl ester (1.49 g)in tetrahydrofuran (50 ml). After a three-hour stirring of the reactionmixture, it is worked up in the usual way and the crude product ischromatographed, melting point 138°-140° C. (cyclohexane).

b)5-(2-Chlorophenoxy)-methyl-4-methoxymethyl-beta-carboline-3-carboxylicacid ethyl ester

Production analogously to F. Neef et al, 1983 Heterocyclus 20, 1295-1313(method a), melting point 67°-68° C.

c)5-(2-Chlorophenoxy)-methyl-4-methoxymethyl-9-tosyl-beta-carboline-3-carboxylicacid ethyl ester

Preparation analogously to example 7B, melting point 149°-152° C.(ethanol)

EXAMPLE 126-Benzyloxy-3-cycloproxylcarbonyl-4-methoxymethyl-beta-carboline

50 mg of6-benzyloxy-3-(1-hydroxy-1-phenylmethyl)-4-methoxymethyl-beta-carbolineis stirred in 10 ml of methylene chloride with 300 mg of manganesedioxide for 1 hour at room temperature. After suctioning off ondiatomaceous earth, the filtrate was concentrated by evaporation and theresidue was chromatographed on silica gel with methylene chloride :ethyl acetate =2:1. 20 mg of the title compound is obtained.

We claim:
 1. A compound of formula I ##STR4## wherein R^(A) is halogen,--CHR¹ --R², phenyl or OR⁵ ;n is 1 or 2; R¹ is hydrogen or C₁₋₄ alkyl;R² is hydrogen, C₁₋₄ alkyl, --O--C₁₋₄ alkyl or substituted orunsubstitued phenyl, benzyl or phenoxy radical; R⁵ is hydrogen, tri-C₁₋₄alkylsilyl, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or substituted or unsubstitutedphenyl, benzyl or hetaryl radical; B is CR⁴ ; R⁴ is unsubstituted orsubstituted monocylic or bicyclic aryl or hetaryl radical or a C₃₋₁₀cycloalkyl or bicycloalkyl radical as well as their isomers; or an acidaddition salt thereof. 2.6-Benzyloxy-4-methoxymethyl-3-benzoyl-beta-carboline,6-(5-bromopyridin-2-yloxy)-4-methoxymethyl-3-benzoyl-beta-carboline,or an acid addition salt thereof.
 3. A pharmaceutical agent comprising acompound of claim 1 and a pharmaceutically acceptable carrier.
 4. Apharmaceutical agent comprising a compound of claim 2 and apharmaceutically acceptable carrier.
 5. A compound according to claim 1,wherein R² is a substituted phenyl, benzyl, or phenoxy substituted byhalogen, nitro, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, amino or C₁₋₄alkoxycarbonyl group.
 6. A compound according to claim 1, wherein R⁵ isa substituted phenyl, benzyl or hetaryl substituted by halogen, nitro,cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, amino or C₁₋₄ alkoxycarbonyl group.
 7. Acompound according to claim 1, wherein R is a substituted aryl orhetaryl substituted by a halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, aminoor nitro group.
 8. A process for the production of a compound accordingto claim 1, comprising reacting a compound of formula II ##STR5##wherein, R^(A) and B have the above-mentioned meaning;R⁹ is a hydrogenor protecting group; Y is a cyano or --CO--Z; and Z is hydrogen, C₁₋₄alkoxy, or an acid derivative;with a metallo-organic compound R-Me; andoptionally, cleaving a trialkylsilyl group to a hydroxy group; oretherifying a hydroxy group to OR⁵ ; or oxidizing R³ =---CH(OH)R to theketone, wherein R has the above-mentioned meaning; or separating theisomers; or forming the acid addition salts.